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CD8+ T cells against multiple tumor-associated antigens in peripheral blood of midgut carcinoid patients

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

The aim of the study was to identify immunogenic HLA-A*0201-binding epitopes derived from a number of classical midgut carcinoid-associated proteins. CD8+ T cells recognizing tumor-associated antigen (TAA) epitopes are of great interest for the establishment of immunotherapy as a novel treatment for this type of malignancy.

Experimental design

Midgut carcinoid tumor specimens were microdissected and expression levels of potential TAAs were investigated by quantitative real time PCR. HLA-A*0201-binding motifs were selected using HLA peptide binding prediction algorithms and stabilization of HLA-A*0201 was verified using TAP-deficient T2 cells. Peripheral blood of midgut carcinoid patients was analyzed for peptide epitope recognition and the feasibility of generating peptide-reactive CD8+ T cells in healthy blood donors was examined by an in vitro stimulation protocol using mature DCs. Activation of patient and healthy donor CD8+ T cells was analyzed by intracellular flow cytometry staining of interferon γ.

Results

Chromogranin A (CGA), tryptophan hydroxylase 1 (TPH-1), vesicular monoamine transporter 1 (VMAT-1), caudal type homeobox transcription factor 2 (CDX-2), and islet autoantigen 2 (IA-2) are properly expressed by midgut carcinoid tumor cells, with CGA mRNA expressed to greatest level. Midgut carcinoid patients have increased frequencies of peripheral blood CD8+ T cells recognizing a pool of HLA-A*0201 peptides derived from these proteins compared to healthy age-matched individuals. Activated peptide-specific CD8+ T cells could also be generated in healthy blood donors by in vitro stimulation.

Conclusion

We have identified a number of immunogenic midgut carcinoid-associated peptide epitopes recognized by CD8+ T cells. We show that midgut carcinoid patients display immune recognition of their tumors. Memory CD8+ T cells in patient blood are of great interest when pursuing an immunotherapeutic treatment strategy.

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Acknowledgments

The authors thank research nurses Monica Hurtig and Lena Olsson at the Clinic of Endocrine Oncology, Uppsala University Hospital for providing the blood samples used in this study. They also thank Dr. Mohammad Alimohammadi, Dept. of Medical Sciences, Uppsala University for sharing valuable peptides. The authors express their gratitude to Verto Institute (Stamford, CT, USA), Dr. Raymond and Beverly Sackler for financial and scientific support.

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Authors and Affiliations

  1. Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    Sofia Vikman, Valeria Giandomenico, Roberta Sommaggio, Magnus Essand & Thomas H. Tötterman

  2. Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden

    Kjell Öberg

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  1. Sofia Vikman
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  2. Valeria Giandomenico
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  3. Roberta Sommaggio
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  4. Kjell Öberg
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  6. Thomas H. Tötterman
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Correspondence to Thomas H. Tötterman.

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Vikman, S., Giandomenico, V., Sommaggio, R. et al. CD8+ T cells against multiple tumor-associated antigens in peripheral blood of midgut carcinoid patients. Cancer Immunol Immunother 57, 399–409 (2008). https://doi.org/10.1007/s00262-007-0382-4

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  • DOI: https://doi.org/10.1007/s00262-007-0382-4

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